Parkinson disease (PD) is an inexorably progressive neurodegenerative disease, whose symptoms include tremor, rigidity and diminishing speed and amplitude of movements. This leads to difficulty walking and impaired social interactions, exacerbated by depression or anxiety. Once thought to predominantly involve dopaminergic neurons in the midbrain, a significant pre-motor phase involving dysfunction of autonomic, olfactory, brainstem and cortical neurons is now recognized. According to data presented at the World Parkinson Congress 2013 up to 35-40% of patients have cognitive dysfunction at the time of initial diagnosis, with dementia eventually afflicting 80% of patients; mood disorders, apathy and delusions may also precede motor symptoms.

We utilize cortical and midbrain neurons, neuroblastoma lines, PD-spectrum patient brain tissues, and mouse models to study mechanisms underlying neurodegeneration in PD. Data from models based on familial PD genes or from toxins that mimic mitochondrial or oxidative stress observed in sporadic human PD tissues are integrated to advance a conceptual framework positing that imbalanced, and thus maladaptive, stress responses permit or contribute to progression of the disease process. In recent years, our emphasis has shifted from neuron cell death to earlier, potentially reversible phases of mitochondrial or axo-dendritic degeneration.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA